Refractoriness of the Cyclic AMP Response to Catecholamines in Rat Parotid Slices In Vitro

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Abstract
Parotid slices respond to norepinephrine [NE] with a rapid but transient accumulation of cAMP. Continued exposure of the slices to norepinephrine causes a loss of responsiveness to subsequent application of NE (refractoriness or desensitization). Refractoriness could not be overcome by exposing the slices to a supramaximum concentration of NE. The suppressed response was clearly seen at 15 min after the 1st exposure to NE, but .apprx. 60 min were required for reaching complete suppression. The refractoriness depended on the concentration of agonists and their order of potency correlated with their agonistic activity. The induction of desensitization was .beta.-agonist specific and was blocked by .beta.-adrenergic blocking agents, e.g., atenolol and alprenolol. The recovery from desensitization was observed by removing NE from the medium. The recovery was not evident until 15 min after washing the slices, but was nearly complete after 1 h. Parallel changes were observed between the initial increase in cAMP level and the degree of desensitization by NE, the induction of desensitization does not seem to be mediated by cAMP. The mechanism underlying this phenomenon does not appear to involve the activation of phosphodiesterase, the formation of an inhibitory substance in the medium or an increase in the rate of excretion of cAMP. Changes in the ATP level by NE did not always correlate with the degree of refractoriness. No significant changes in the amount of [3H]-dihydroalprenolol binding were found in the membrane fraction prepared from the slices incubated with NE. The induction of desensitization may be mediated by modulating the coupling process between the receptor and adenylate cyclase.